Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates

Nat Chem. 2016 Dec;8(12):1112-1119. doi: 10.1038/nchem.2635. Epub 2016 Oct 17.

Abstract

The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein. Using a concise, protecting-group-free synthesis we demonstrate the chemoselective modification of 12 complex molecules that contain a range of reactive functional groups. We also show the utility of this connection with both protease-cleavable and reductively cleavable antibody-drug conjugates that were effective and stable in vitro and in vivo. Studies with a tertiary-amine-containing antibiotic show that the resulting antibody-antibiotic conjugate provided appropriate stability and release characteristics and led to an unexpected improvement in activity over the conjugates previously connected via a carbamate.

MeSH terms

  • Amines / chemistry*
  • Anti-Bacterial Agents / chemistry
  • Antibodies, Monoclonal / chemistry*
  • Antineoplastic Agents / chemistry
  • Cathepsins / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Carriers / chemistry*
  • Drug Liberation
  • Drug Stability
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunoconjugates / chemistry
  • Immunoconjugates / metabolism*
  • Immunoconjugates / pharmacology
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism
  • Quaternary Ammonium Compounds / chemistry
  • Solubility

Substances

  • Amines
  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Drug Carriers
  • Immunoconjugates
  • Pharmaceutical Preparations
  • Quaternary Ammonium Compounds
  • Cathepsins